Patients with impaired renal function develop an abnormal phosphate metabolism. The pathomechanism of hyperphosphatemia in patients with reduced renal function is a complex dysregulation of glomerular filtration, tubular reabsorption, and release from bone caused by a hormonal imbalance. In conjunction with calcium imbalance, hyperphosphatemia increases the risk of cardiovascular disease in patients with impaired renal function. Hyperphosphatemia promotes arterial calcification, increasing the risk of myocardial infarction and stroke in these patients (Hruska et al., 2008).
In early renal dysfunction, hyperphosphatemia can be addressed by reducing dietary phosphate intake, but this measure has the disadvantage of being associated with a deficient uptake of essential nutritional components. Therefore drugs are available for treating hyperphosphatemia by reducing phosphate absorption from food. These drugs can be taken orally and bind free phosphate in the gastrointestinal tract, forming insoluble complexes or aggregates that are excreted with the feces (Coladonato, 2005).
Since patients with impaired renal function require lifelong medication for controlling hyperphosphatemia, there are three basic requirements a phosphate binder must meet:
1) The drug must be safe and ideally should have no adverse effects.
2) Phosphate binding must be high relative to dose.
3) Costs must be low so that the drug is available to all patients who need it.
The most common drugs that bind phosphate in the gastrointestinal tract are based on calcium salts such as calcium acetate and calcium carbonate. Calcium-based phosphate binders are inexpensive but have considerable adverse effects, most notably an increase in calcium serum levels, which in turn accelerates vascular calcification. In advanced kidney failure, adequate control of hyperphosphatemia using calcium-based phosphate binders can only be achieved at the cost of considerable adverse effects.
Sevelamer, which is based on polyallylamine, is more effective and is better tolerated. However, current reimbursement practices in the healthcare sector preclude lifelong treatment of all patients with this drug.
Serum phosphate levels can be lowered most effectively by aluminium hydroxide. This agent is only approved for short-term use in lowering very high serum phosphate levels. Aluminium is absorbed in the gastrointestinal tract, and this absorption has been shown to be associated with encephalopathy and bone demineralization (Wills and Savory, 1989).
Lanthanum carbonate is an effective oral phosphate binder and is available at a reasonable price. However, this drug is associated with predominantly gastrointestinal adverse effects, including obstipation, which requires discontinuation of lanthanum carbonate and switching to an alternative phosphate binder. Moreover, it is assumed that small amounts of lanthanum ions are absorbed in the gastrointestinal tract, contributing to the induction of lanthanum-associated nephrogenic systemic fibrosis. This new condition has only been observed in patients with reduced kidney function who received a gadolinium-based contrast agent for magnetic resonance imaging. In these patients, the longer residence time of the contrast agent in the body leads to release of the lanthanide gadolinium from the contrast agent complex, causing therapy-refractory inflammation of connective tissue structures throughout the body. Nephrogenic systemic fibrosis has so far only been observed in countries where the lanthanum-based phosphate binder Fosrenol is approved, suggesting a synergistic effect of both lanthanides (Brambilla et al., 2008).
New phosphate binders on the basis of iron oxide crystals that can be administered orally are currently undergoing clinical testing of effectiveness. These include ferrihydrite, iron hydroxide, and iron oxyhydroxides such as goethite (alpha-iron oxyhydroxide), akaganeite (beta-oxyhydroxide), and lepidocrocite (gamma-iron oxyhydroxide).
WO 92/01458 describes a method for controlling serum phosphate levels and for treating and preventing hyperphosphatemia. The method consists in oral administration of phosphate-binding oxy-iron compounds (iron oxides and iron oxy-hydroxides), especially synthetic ferrihydrite (Fe5O7(OH)), for inhibiting phosphate uptake from food.
WO 2006/000547 A2 describes an iron-hydroxide-based phosphate adsorbent prepared from iron(III) sulfate and/or iron(II) nitrate.
WO 2008/071747 A1 discloses a phosphate adsorbent on the basis of polynuclear iron(III) oxide-hydroxide and a soluble carbohydrate partially incorporated into the polynuclear iron(III) oxide-hydroxide and further comprising an adsorbent base material, preferably an insoluble carbohydrate, which is intended for treatment of hyperphosphatemia.
Iron(III) ions are a further basis for metal-based phosphate adsorbers. In experimental studies a high phosphorus binding capacity was found for iron(III) citrate, iron(III) chloride or iron(III) ammonium citrate (Hsu et al, 1999). The production and the use of a pharmaceutical grade iron(III) citrate as an oral phosphate binding drug to treat elevated serum phosphate levels has been laid down by Kwok et al. in U.S. Pat. No. 7,767,851 B2. However, a major drawback of highly soluble iron salts or chelates is the release of free iron ions, leading biochemically to oxidative stress with a high risk of iron toxicity (Somers, 1947). Additionally in patients treated against hyperphosphatemia nearly a life long there is the risk of systemic iron overload due to intestinal iron resorption of the free iron ions, which has been shown for iron(III) citrate (Heinrich, 1987). This results in a limited risk to benefit ratio for these type of iron compounds as phosphate adsorbers.
From geological research and waste water processing, the phosphate-binding capacity of iron oxides, iron hydroxides, and iron oxyhydroxides is known in the art (Daou et al., 2007).
US 2009/0309597 A1 discloses superparamagnetic nanoparticle probes based on iron oxides, such as magnetite or maghemite, with modified surface, coated with mono-, di- or polysaccharides or with amino acids or poly(amino acid)s or with synthetic polymers based on (meth)acrylic acid and their derivatives, which form a colloid consisting of particles with an average size of 0.5-30 nm, having an iron content of 70-99.9 wt. %, preferably 90 wt. %, and having a content of modification agent of 0.1-30 wt. %, preferably 10 wt. %. The nanoparticle probes are suitable as diagnostic probes, such as for the in vitro labelling of cells.
EP 0 525 199 A1 discloses compositions containing ultrafine particles of a magnetic metal oxide, which comprise an aqueous sol of a composite consisting of the ultrafine particles and a polysaccharide, its derivative and/or a protein, and an organic monocarboxylic acid. The compositions are suitable as MRI contrast agents.
There is a need in the prior art for improved phosphate-binding agents and methods of administration.
The present invention therefore aims to provide efficient, easy to manufacture, and well tolerated oral phosphate binders that, among other things, can improve the treatment of hyperphosphatemia.
Before the present invention is described in more detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. For the purpose of the present invention, all references cited herein are incorporated by reference in their entireties.
Numbers or other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “2 to 20 nm” should be interpreted to include not only the explicitly recited values of 2 to 20, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 nm and sub-ranges such as from 2 to 5 nm, from 2 to 10 nm, from 2 to 8 nm etc. As an illustration, a numerical range of “about 3 to 50 wt-%” should be interpreted to include not only the explicitly recited values of 3 to 50, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 3, 4, 5, 6, 7, . . . 48, 49, 50 and sub-ranges such as from 3 to 45, 5 to 45, 10 to 45, 15 to 45, 3 to 40, 5 to 40, 10 to 40, 15 to 40, 3 to 35, 5 to 35, 10 to 35, 15 to 35, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
Phosphate Adsorbent with Inverse Spinel Iron Oxide Core and Coating(s)
The object is solved according to the invention by providing a phosphate adsorbent comprising
(i) an iron oxide core comprising an inverse spinel iron oxide crystal structure,
(ii) a coating selected from (a) monosaccharides or disaccharides, or (b) alditols, or mixtures thereof,
and/or
(iii) a pharmaceutical excipient selected from polymeric carbohydrates.
The phosphate adsorbent according to the invention has the form of nanoparticles.
The nanoparticles have a particle size of the iron oxide core (i) of less than/smaller than 20 nm, preferably less than/smaller than 10 mm.
The nanoparticles have a particle size of the iron core (i) of preferably 2 to 20 nm, more preferably 2 to 5 nm.
The phosphate adsorbent according to the present invention is based on maghemite or a mixture of maghemite and magnetite.
The phosphate adsorbent according to the present invention is not based on iron citrate or ferric citrate.
The use of phosphate binders on the basis of iron oxide crystals has several advantages for patients with impaired renal function. Iron-based medications for treating hyperphospatemia can be manufactured at low cost, and adverse events are not likely to occur. Patients on hemodialysis generally require iron replacement therapy since considerable amounts of iron are eliminated by hemodialysis treatment. Hence, potential gastrointestinal absorption of small amounts of iron is not an undesired adverse effect. On the contrary, it even has a therapeutic benefit in this patient population compared with the undesired risks associated with aluminium, calcium, or lanthanide from other phosphate binders.
There are some basic requirements for a phosphate binder based on iron oxide crystals:
1) The type of iron oxide crystal used has to ensure optimal phosphate adsorption.
2) The crystallite size has to be as small as possible to provide a large adsorptive surface area.
3) The individual crystals should preferably have a coating that can be displaced by phosphate, while providing long enough stability in the digestive tract.
4) It is preferred that a galenic formulation and the dosage form ensure optimal mixture of the iron-oxide-crystal-based phosphate adsorbent with body fluids and food components in the digestive tract.
The phosphate adsorbent according to the invention preferably has an iron content which is about
3 to 50 wt-% of total weight of the phosphate adsorbent,
3 to 45 wt-% of total weight of the phosphate adsorbent,
5 to 45 wt-% of total weight of the phosphate adsorbent,
10 to 45 wt-% of total weight of the phosphate adsorbent,
15 to 45 wt-% of total weight of the phosphate adsorbent,
3 to 40 wt-% of total weight of the phosphate adsorbent,
5 to 40 wt-% of total weight of the phosphate adsorbent,
10 to 40 wt-% of total weight of the phosphate adsorbent,
15 to 40 wt-% of total weight of the phosphate adsorbent,
3 to 35 wt-% of total weight of the phosphate adsorbent,
5 to 35 wt-% of total weight of the phosphate adsorbent,
10 to 35 wt-% of total weight of the phosphate adsorbent.
15 to 35 wt-% of total weight of the phosphate adsorbent,
(i) Iron Oxide Core
The iron oxide core of the phosphate adsorbent according to the present invention comprises an inverse spinel iron oxide crystal structure.
Iron oxide crystals of the inverse spinel type have the highest phosphate binding capacity of all iron oxides in relation to the crystal surface area (Daou et al., 2007, Barber 2002). There are only two inverse spinel iron oxides: magnetite (Fe3O4) and its oxidized form, maghemite (gamma-Fe2O3). It is known that maghemite has a higher phosphate-binding capacity than magnetite in relation to the surface area available for adsorption.
The use of iron oxides of the inverse spinel type for phosphate adsorption from food or fluids in the digestive tract has not been investigated or even considered. Suitable particle dispersions on the basis of inverse spinel iron oxides are not known, have not been manufactured, and/or have not been tested for this purpose.
Inverse spinel iron oxides have a crystal structure that is distinct from that of all other iron oxides. This structure is characterized by cubic close packed oxygen atoms with tetrahedral and octahedral positions for iron ions according to crystallographic nomenclature. One unit cell consists of 32 oxide ions with 64 tetrahedal sites and 32 octahedral sites. In the inverse spinel iron oxide magnetite, ferric ions occupy ⅛ of the tetrahedral sites and ¼ of the octahedral sites. In maghemite, the oxidized form of magnetite, the arrangement of oxide ions is the same as in magnetite. However, in contrast to magnetite, ⅛ of tetrahedral sites and ½ of octahedral sites are occupied by 21⅓ ferric ions with 2⅓ of sites remaining vacant. Hence, maghemite is a defect inverse spinel iron oxide in relation to magnetite.
In a preferred embodiment, the phosphate adsorbent according to the invention is monocrystalline.
A monocrystal, or single crystal, is a macroscopic crystal characterized by an entirely regular arrangement of its components (atoms, ions, or molecules). This arrangement distinguishes a monocrystal from polycrystalline aggregates, twinned crystals, or amorphous substances.
In a preferred embodiment, the phosphate adsorbent according to the invention is mononuclear. According to the present invention, “mononuclear” is used to mean that the monocrystals do not aggregate. This is important to ensure that the required or desired surface area is available for phosphate adsorption.
In a preferred embodiment, the phosphate adsorbent according to the invention is monodisperse, meaning that the nanoparticle sizes are within a predefined size range (especially a particle size of the iron oxide core (i) of less than 20 nm, preferably of less than 10 nm; especially a particle size of the iron oxide core (i) of preferably 2 to 20 nm, more preferably 2 to 5 nm).
In a preferred embodiment, the iron oxide core (i) of the phosphate adsorbent according to the invention comprises (nanoscale) inverse spinel iron oxide with over 90% having the same crystallite size (i.e., a particle size of the iron oxide core (i) of less than 10 nm, preferably less than 5 nm, more preferably 2 to 5 nm).
In a preferred embodiment, the iron oxide core (i) of the phosphate adsorbent according to the invention consists of (nanoscale) inverse spinel iron oxide with over 90% having the same crystallite size (i.e., a particle size of the iron oxide core (i) of less than 10 nm, preferably less than 5 nm, more preferably 2 to 5 nm).
In a preferred embodiment, the iron oxide core (i) comprises monocrystalline maghemite with less than 20 weight percent of magnetite or consists of monocrystalline maghemite with less than 20 weight percent of magnetite.
Pure magnetite has 30% ferrous ions expressed in relation to total iron (molar ratio). Expressing the proportion of ferrous iron in relation to total iron as a molar ratio is equivalent to giving the percentage weight since ferrous iron has one electron more than ferric iron, which is negligible relative to total mass.
It is preferred that the iron oxide core (i) according to the invention comprises inverse spinel iron oxide with less than 20% ferrous ions in relation to total iron (molar ratio), preferably less than 15%, more preferably less than 10%, even more preferably less than 5% or less than 3% (molar ratio). In a preferred embodiment, the proportion of ferrous iron is less than 5%, more preferably less than 3% (molar ratio).
In one embodiment, the iron oxide core (i) further comprises hematite, goethite, lepidocrocite, akaganeite, and/or ferrihydrite in a weight proportion of less than 20% in relation to total iron.
The phosphate adsorbent according to the invention is available in the following embodiments:                Iron oxide core (i) with coating (ii);        Iron oxide core (i) with pharmaceutical excipient (iii);        Iron oxide core (i) with coating (ii) and pharmaceutical excipient (iii).        
(ii) Primary Coating
The phosphate adsorbent according to the invention preferably comprises a coating (ii) comprising:                (a) mono- or disaccharides,        (b) alditols,        or mixtures thereof.        
The coating (ii) is the primary coating of the iron oxide cores (i).
The individual crystals (i.e., the iron oxide cores (i)) require a sheath/coating that can be displaced by phosphate while providing long enough stability in the gastrointestinal tract.
The surface of iron oxides of the inverse spinel type is highly adsorptive, and the particles aggregate in aqueous dispersion when they lack a suitable coating. This is why the individual crystals require a coating in order to be used as a phosphate binder in the gastrointestinal tract. A major hypothetical prerequisite is that the coating should ideally only be displaceable by phosphate and interact as little as possible with other substances and molecules present in the fluids of the gastrointestinal tract.
In addition to these requirements regarding the coating, the individual crystals must be as small as possible to maximize the adsorptive surface area relative to the total iron content. Known and commercially available drugs on the basis of inverse spinel iron oxide such as Resovist®, with ferucarbotran as the active agent, and Feraheme®, with ferumoxytol as the active agent, are based on maghemite crystals with a coat of polymer carboxydextran, and, in the form of highly stable dispersions, are approved for intravenous administration as a contrast agent for magnetic resonance imaging (Resovist®) or as a therapeutic drug for treating iron deficiency anemia (Feraheme®). In addition, numerous production methods and preparations of inverse spinel iron oxides with crystallite sizes of less than 20 nm are known. These are kept in stable aqueous dispersion by highly stabilizing coatings consisting of citrate, tartrate, glucuronic acid, or glutamic acid and can also be administered intravenously. In comparative examples 3 and 4, these highly stable dispersions show very strong interaction between the coating and the iron oxide core with only little displacement by phosphate. This is why these inverse spinel iron oxides with very stable coatings, which are already in use as drugs in humans or under clinical investigation for use in humans, appear not to be well suited for controlling hyperphosphatemia by adsorbing phosphate in the digestive tract.
The aliphatic or cyclic mono- or disaccharides (a) of the coating according to the invention (ii) are preferably selected from mono- or disaccharides of aliphatic and/or aromatic hexoses or pentoses. These are further preferably selected from mannose, saccharose, fructose, fucose, trehalose, glucose, rhamnose, galactose, maltose, and arabinose.
A preferred embodiment of the (primary) coating (ii) comprises mannose, maltose, and/or saccharose, or consists of mannose, maltose, and/or saccharose.
The alditols (b), or sugar alcohols, of the coating (ii) according to the invention are preferably selected from mannitol, sorbitol, isomalt, threitol, lactitol, xylitol, arabitol, erythritol, and glycerol, more preferably from mannitol.
In a preferred embodiment, the (primary) coating (ii) does not comprise or consist of citrate, tartrate, glucuronic acid, or glutamic acid. These compounds/substances have a carboxyl group, which results in too strong bonding to the surface of the iron oxide cores, precluding adequate displacement by phosphate.
In a preferred embodiment, the (primary) coating (ii) does not comprise or consist of saturated or unsaturated fatty acids or tensides.
Also preferred are mixtures of aliphatic or cyclic mono- or disaccharides (a) with alditols (b).
Mixtures of aliphatic or cyclic mono- or disaccharides with mannitol are particularly preferred for intravenous administration.
In a preferred embodiment, the coating (ii) is in excess of the binding sites on the iron oxide crystal surface (of the iron oxide cores (i)).
The coating (ii) prevents mutual aggregation of the iron oxide crystals and undesired interactions with components of physiological fluids in the gastrointestinal tract and food components in the gastrointestinal tract while at the same time being displaceable by inorganic phosphate. The coating (ii) interacts with the iron oxide surface in the form of van der Waals forces, electrostatic attraction, salt formation, or complex formation. In order to ensure adequate enclosure by the coating (ii), a molar excess of the coating (ii) in relation to the binding sites on the iron oxide crystal surface in accordance with the thermodynamic behavior of said interactions must be available during production of the iron-based phosphate adsorbent according to the invention and after resuspension for use as a drug.
This is reliably accomplished during the production of the phosphate adsorbent according to the invention by:
(1) adding the coating (ii) during the crystallization process in a ratio to total iron (sum of ferrous and ferric ions) at a molar excess of at least 1.2 (up to 10-fold excess), preferably 2- to 5-fold molar excess, for example 3-fold excess (see example 1);
(2) optionally adding the coating (ii) after the purification steps (dialysis, ultrafiltration, centrifugation, diafiltration) in an amount that corresponds to between 5 and 20% of the amount initially used in the primary reaction mixture.
(iii) Pharmaceutical Excipient
The phosphate adsorbent according to the invention preferably comprises a pharmaceutical excipient (iii).
The excipient according to the invention (iii) serves as a (secondary) coating and for the pharmaceutical formulation of the phosphate adsorbent according to the invention.
The excipient is added to obtain a galenic formulation for optimal dispersion in physiological fluids of the digestive tract and food in the digestive tract.
Galenic formulation and the dosage form serve to ensure optimal mixture of the iron-oxide-crystal-based phosphate adsorbent.
The excipient according to the invention (iii) is selected from polymeric carbohydrates.
The pharmaceutical excipient (iii) is preferably selected from                glucans such as dextran, starch, cellulose, polymaltose, dextrin, glycogen, pullulan, carboxymethyl cellulose,        fructans such as inulin,        and gum arabic,        or mixtures thereof.        
More preferably, the pharmaceutical excipient (iii) is selected from fructans, especially inulin.
Preferred mixtures are mixtures of fructan(s) such as inulin with glucan(s) such as starch and/or carboxymethyl cellulose.
Other preferred mixtures are mixtures of fructan(s) such as inulin with gum arabic, especially inulin with gum arabic.
Examples 1 to 5 show that pharmaceutical preparations with a combination of inulin and gum arabic achieve particularly high phosphate adsorption, as seen from examples 1, 1b, 5a, and 5g. Comparison of phosphate adsorption in examples 1 and 2 clearly shows that the combination of inulin and gum arabic used as a pharmaceutical excipient is especially effective since a higher phosphate adsorption was found in example 1 compared with example 2, where inulin was used alone.
Further Components
The phosphate adsorbent according to the invention preferably can comprise further components, which preferably increase the phosphate binding capacity.
In one embodiment, the further component is ascorbic acid.
In one embodiment, ascorbic acid added to the phosphate adsorbens in final drug formulation for pH adjustment with the property of an enhancement of the total phosphate adsorption capacity, such as it is shown in example 7b. The increase of phosphate binding capacity due to the addition of ascorbic acid is not only related to pH lowering because pH lowering alone using hydrochloric acid as shown in example 7c results in a minor phosphate adsorption compared to example 7b.
In one embodiment, the further component is gelatine.
For example, the final drug application form of the phosphate adsorbent according to the invention comprising gelatine, preferably an aqueous gelatine preparation (such as gelatine with a gel strength between 10 and 300 Bloom gel strength units), is an oral dosage form, preferably in the form of a gel, gel caps or jelly beans. Said final drug application form of the phosphate adsorbent according to the invention results in further increase of the patient compliance, drug tolerance and an enhancement of the phosphate binding capacity, such as shown in example 7d.
Phosphate Binding Capacity
The phosphate adsorbent according to the invention preferably has a phosphate binding capacity of at least 300 mg phosphate per gram of iron, preferably over 500 mg/g of iron.
Phosphate adsorbents described in the prior art have a much lower phosphate-binding capacity, such as shown in FIG. 2.
See examples. Example 1 shows adsorption of 640 mg of phosphate per gram of iron in Nutricomp MCT simulated gastrointestinal contents. Comparative example 1 (according to WO 2006/000547 A2, example 3) shows adsorption of 240 mg of phosphate per gram of iron in Nutricomp MCT. Comparative example 2 (according to WO 2008/071747, example 2), showed adsorption of 225 mg of phosphate per gram of iron.
Further example 7a shows an adsorption of 480 mg per gram iron in Nutricomp MCT which is further enhanced by the addition of ascorbic acid to a maximum of 1310 mg bound phosphate per gram iron. A final drug application gel form using gelatin as the pharmaceutical drug vehicle has an adsorption of 1140 mg phosphate per gram iron.
Reduction of Iron Release
The phosphate adsorbent according to the invention preferably has an iron release of less than 10% of the total iron input.
In one embodiment, the phosphate adsorbent according to the invention preferably has an iron release of less than 8%, more preferably less than 5% of the total iron input, such as less than 2% or less than 1% of the total iron input, such as about 1.5% or about 1% or about 0.5%.
Phosphate adsorbents described in the prior art with an phosphate adsorption above 500 mg phosphate per gram iron in Nutricomp MCT, such as described in comparative example 8 (according to U.S. Pat. No. 7,767,851 B2) and 9 show an iron ion release in relation to total iron input of 30.6% and 17% respectively. In contrast to this example 1, 7a-d exhibit an iron ion release less than 2 and 1% respectively.
Method for the Production of the Phosphate Adsorbent
The object is solved according to the invention by a method for producing a phosphate adsorbent.
Production of the Phosphate Adsorbent with (Primary) Coating (ii)
The method according to the invention comprises alkaline precipitation of iron(II) and iron(III) salt solutions with a base in the presence of a carbohydrate matrix, which, according to the invention, is a compound selected from (a) mono- or disaccharides or (b) alditols or mixtures thereof (with the said carbohydrate matrix or compound forming the coating (ii) of the iron oxide cores (i)).
The base is preferably selected from NaOH, KOH, or ammonium hydroxide or mixtures thereof.
The phosphate adsorbent prepared according to the invention is based on maghemite or a mixture of maghemite and magnetite.
Preferably, the iron(II) and iron(III) salt solutions are solutions of iron(II) chloride and iron(IIII) chloride.
Alkaline precipitation is preferably performed at a temperature of 0 to 25° C., preferably 0 to 20° C., more preferably 4 to 12° C.
The iron(II) and iron(III) ions are preferably present in a molar ratio of 0.4 to 0.7, more preferably in a molar ratio of 0.5 to 0.66.
Alkaline precipitation is performed in the presence of a compound selected from (a) mono- or disaccharides or (b) alditols or mixtures thereof.
The aliphatic or cyclic mono- or disaccharides (a) are preferably selected from mono- or disaccharides of aliphatic and/or aromatic hexoses or pentoses, more preferably from mannose, saccharose, fructose, fucose, trehalose, glucose, rhamnose, galactose, maltose, and arabinose, and even more preferably from mannose, maltose, and/or saccharose.
The alditols (b), or sugar alcohols, are preferably selected from mannitol, sorbitol, isomalt, threitol, lactitol, xylitol, arabitol, erythritol, and glycerol, more preferably from mannitol.
In a preferred embodiment, the compound is present in excess (in molar excess in relation to iron), with “in excess” referring to the molar ratio of the compound to the available binding sites on the iron oxide crystal surfaces (of the iron oxide cores (i)).
The iron oxide cores (i) and the coating (ii) are in thermodynamic equilibrium, i.e., bound in complexes and in solution/dispersion. An excess of compound (ii) increases the likelihood of the surfaces of the iron oxide cores being coated; which is advantageous for preventing undesired aggregate formation of iron oxide particles with unsaturated. As outlined above, the coating (ii) (which forms from the compound present during production according to the invention) prevents mutual aggregation of the iron oxide crystals and undesired interactions with components of physiological fluids in the gastrointestinal tract and food contents in the gastrointestinal tract, while at the same time being displaceable by inorganic phosphate.
As also outlined above, the interaction between the iron oxide surface and the compound (ii) may be based on salt formation, van der Waals forces, complex formation, and other electrostatic interactions, and it may be based on covalent bonding. Interactions of the compound (ii) with the iron oxide surfaces result in a thermodynamic equilibrium between free compound in the solution and compound bound to iron oxide surfaces according to chemical and physical laws. In order to ensure adequate coating of the iron oxides by the compound (ii) and to ensure reliable stabilization of the dispersion of iron oxide crystals during production and handling, it is necessary that the compound forming the coating is present in molar excess relative to the potentially available binding sites on the iron oxide surfaces. This is reliably accomplished if, in the production procedure, the compound (ii) is present during the primary crystallization reaction in a ratio of primary coating molecules to total iron of at least 1:1.2 (up to approx. 10-fold excess, preferably 2- to 5-fold molar excess). Better results in terms of phosphate binding are achieved if—as shown in example 1—the molar ratio of primary coating material to total iron during primary crystallization in the production process is for instance is a three fold excess.
As also outlined above, the said molar excess of the compound (ii) is achieved during the production of the phosphate adsorbent according to the invention by: (1) adding the compound/coating (ii) during the crystallization process in a ratio to total iron (sum of ferrous and ferric iron) at a molar excess of at least 1.2 (up to 10-fold excess), preferably 2- to 5-fold molar excess, for example 3-fold excess (see example 1);
(2) optionally adding additional compound/coating (ii) after the purification steps (dialysis, ultrafiltration, centrifugation, diafiltration) in an amount that corresponds to between 5 and 20% of the amount initially used in the primary reaction mixture.
Process Steps
A method according to the invention preferably comprises these steps:
(1) Preparation of an aqueous solution of iron(II) and iron(III) salts, especially iron(II) chloride and iron(III) chloride.
(2) Preparation of an aqueous solution of a compound selected from
(a) (aliphatic or cyclic) mono- or disaccharides (preferably selected from mono- or disaccharides of aliphatic and/or aromatic hexoses or pentoses such as mannose, saccharose, fructose, fucose, trehalose, glucose, rhamnose, galactose, maltose, and arabinose, or
(b) alditols (preferably selected from mannitol, sorbitol, isomalt, threitol, lactitol, xylitol, arabitol, erythritol, and glycerol, more preferably from mannitol), or mixtures thereof.
(3) Combining of solutions (1) and (2) and addition of a base to obtain a suspension with pH of 7 to 13.
The base is preferably selected from NaOH, KOH, or ammonium hydroxide or mixtures thereof.
The temperature is 0 to 25° C., preferably 0 to 20° C., more preferably 4 to 12° C.
The compound in step (2) is preferably selected from mannose, maltose, saccharose, and/or mannitol.
The compound in step (2) is preferably available in excess, as described above.
The compound in step (2) is preferably available in molar excess relative to total iron (sum of ferrous and ferric iron) of at least 1.2 (up to 10-fold excess), preferably 2- to 5-fold molar excess, for example 3-fold excess.
A method according to the invention further preferably comprises step (4):
(4) Oxidation by adding an oxidizing agent and/or introducing air or pure oxygen gas at a temperature between 25° C. and 90° C., preferably 40 and 65° C.
The preferred oxidizing agent is hydrogen peroxide or nitric acid in combination with iron nitrate.
In step (4), magnetite is oxidized to form maghemite. This is an important step, since without this measure, oxidation would occur spontaneously over weeks, with release of reactive iron, which may be toxic or result in an unstable dispersion.
In addition to ensuring optimal phosphate binding, an iron-based phosphate adsorbent must be highly stable to minimize release of iron from the crystals. Magnetite from the group of inverse spinel iron oxides easily oxidizes and hence is less stable. Without controlled oxidation, magnetites would undergo spontaneous oxidation during storage, releasing ferrous and ferric ions, which might cause undesired adverse effects when such a preparation is used in patients. It is therefore necessary and preferred to perform a controlled oxidation and to remove any iron ions released during this reaction. Oxidation can be induced by adding hydrogen peroxide as an oxidizer in aqueous solution or by introducing room air or pure oxygen into the aqueous solution. Iron ions released during oxidation are preferably separated and removed in a further step (see step (5)) using sedimentation of the magnetic dispersion with a magnet or centrifugation and withdrawal of the supernatant. Moreover, these reaction products can be removed by dialysis, ultrafiltration, or diafiltration.
A method according to the invention further preferably comprises step (5):
(5) Removal of unbound iron(II) ions and/or iron(III) ions by centrifugation, dialysis, magnetic separation, and/or ultrafiltration.
A method according to the invention further preferably comprises step (6):
(6) Addition of a pharmaceutical excipient selected from polymeric carbohydrates.
The pharmaceutical excipient (iii) is preferably selected from                glucans, such as dextran, starch, cellulose, polymaltose, dextrin, glycogen, pullulan, carboxymethyl cellulose,        fructans, such as inulin,        and gum arabic,        or mixtures thereof.        
More preferably, the pharmaceutical excipient (iii) is selected from fructans, especially inulin.
Preferred mixtures are mixtures of fructan(s), such as inulin, with glucan(s), such as starch and/or carboxymethyl cellulose.
Further preferred mixtures are mixtures of fructan(s), such as inulin, with gum arabic, especially inulin with gum arabic.
The pharmaceutical excipient is added to provide a secondary coating and to ensure pharmaceutical formulation of the phosphate adsorbent according to the invention as described herein. The addition of the excipient primarily enables drying to a fine powder.
The preferred amount of excipient to be added is such that the total iron content of the resulting phosphate adsorbent is between 100 and 300 mg in the dried state.
In one embodiment of the method according to the invention, in step (6) the compound from step (2) (the coating (ii)), is added again, either simultaneously with the excipient or separately.
Thereby, in step (6), the preferred amount of the compound from step (2) (the coating (ii)) to be added is less than 2 weight % of the amount of the compound (ii) initially added according to step (2).
In one embodiment, the method according to the invention comprises a washing step (preferably after step (6)) using the compound from step (2) for washing.
Washing is performed with an aqueous solution of the compound from step (2) at a concentration between 2 and 5% (weight/volume). This washing step serves to remove undesired reaction products after step 6 in order to prevent removal of too large a proportion of stabilizing compounds (ii) or (iii), thereby precluding possible undesired aggregation of the iron oxide crystals.
A method according to the invention further preferably comprises step (7):
(7) Drying of the resulting suspension using lyophilization and/or heat drying.
Production of the Phosphate Adsorbent without (Primary) Coating (ii)
In one embodiment the phosphate adsorbent according to the invention comprises iron oxide cores (i) with a pharmaceutical excipient (iii).
According to the invention, the method for producing this embodiment corresponds to the method described hereinabove except that step (2) is left out and step (3) below is performed instead:
(3) Addition of a base to solution (1) to obtain a suspension with a pH of 7 to 13.
The base is preferably selected from NaOH, KOH, or ammonium hydroxide or mixtures thereof.
As described above, the method according to the invention comprises the following steps
(1) Preparation of an aqueous solution of iron(II) and iron(III) salts
(2) left out,
(3) Addition of a base, selected from NaOH, KOH, or ammonium hydroxide or mixtures thereof, to solution (1) to obtain a suspension with a pH of 7 to 13, at a temperature between 0 to 25° C., preferably 0 to 20° C.
As described above, the method according to the invention further comprises the following step(s):
(4) Oxidation by adding an oxidizing agent and/or introducing air or pure oxygen gas at a temperature between 25° C. and 90° C., preferably between 40 and 65° C. and/or
(5) Removal of unbound iron(II) and/or iron(III) ions by centrifugation, dialysis, magnetic separation, and/or ultrafiltration. and/or
(6) Addition of a pharmaceutical excipient selected from polymeric carbohydrates,                preferably selected from        glucans such as dextran, starch, cellulose, polymaltose, dextrin, glycogen, pullulan, carboxymethyl cellulose,        fructans such as inulin,        and gum arabic,        or mixtures thereof.        
and/or
(7) Drying of the resulting suspension using lyophilization and/or heat drying.
According to the invention, the iron oxide cores of the inverse spinel type (i) can also be produced without primary coating (ii) and used as phosphate adsorbent. The phosphate adsorbent prepared in this way (see example 6) has lower phosphate adsorption compared with the same phosphate adsorbent produced with a coating of compound (ii) (as in example 1); however, the phosphate-binding capacity of this uncoated form is higher/better than that of known iron-hydroxide-based phosphate adsorbents (see for instance comparative examples 1 and 2).
Product of the Method
The object is solved according to the invention by providing a phosphate adsorbent obtained by a method according to the invention, as described herein.
The object is solved according to the invention by providing a phosphate adsorbent according to the invention, as described herein, obtained by a method according to the invention, as described herein.
According to the invention, the resulting phosphate adsorbent has the form of nanoparticles.
According to the invention, the nanoparticles have a particle size of the iron oxide core (i) of less than/smaller than 20 nm, preferably less than/smaller than 10 nm.
According to the invention, the nanoparticles have a particle size of the iron oxide core (i) of preferably 2 to 20 nm, more preferably 2 to 5 nm.
According to the invention, the resulting phosphate adsorbent has an iron content which is about
3 to 50 wt-% of total weight of the phosphate adsorbent, such as
3 to 45 wt-% of total weight of the phosphate adsorbent,
5 to 45 wt-% of total weight of the phosphate adsorbent,
10 to 45 wt-% of total weight of the phosphate adsorbent,
15 to 45 wt-% of total weight of the phosphate adsorbent,
3 to 40 wt-% of total weight of the phosphate adsorbent,
5 to 40 wt-% of total weight of the phosphate adsorbent,
10 to 40 wt-% of total weight of the phosphate adsorbent,
15 to 40 wt-% of total weight of the phosphate adsorbent,
3 to 35 wt-% of total weight of the phosphate adsorbent,
5 to 35 wt-% of total weight of the phosphate adsorbent,
10 to 35 wt-% of total weight of the phosphate adsorbent.
15 to 35 wt-% of total weight of the phosphate adsorbent,
Pharmaceutical Compositions
The object is solved according to the invention by providing a pharmaceutical composition comprising a phosphate adsorbent according to the invention, as described herein.
The object is solved according to the invention by providing a pharmaceutical composition comprising a phosphate adsorbent according to the invention obtained by a method according to the invention, as described herein.
A pharmaceutical composition according to the invention optionally comprises further pharmaceutically active excipient(s), such as silicium oxide, talcum, gelatin, polyethylene glycol, magnesium oxide, magnesium carbonate, chitosan.
A pharmaceutical composition according to the invention optionally comprises one or several further active agent(s) such as iron hydroxide (e.g., hematite, goethite, akaganeite, lepidocrocite), lanthanum carbonate, calcium acetate, magnesium carbonate, or sevelamer.
In one embodiment, a pharmaceutical composition according to the invention comprises ascorbic acid as further active ingredient.
The pharmaceutical excipient (iii) of the phosphate adsorbent is preferably selected from fructans, such as inulin, or is a mixture of fructan, especially inulin, with gum arabic as a galenic formulation.
A pharmaceutical composition according to the invention optionally comprises pharmaceutical vehicle(s) or carrier(s).
In one embodiment, a pharmaceutical composition according to the invention comprises gelatine as a pharmaceutical vehicle.
The gelatine is preferably an aqueous gelatine preparation, preferably gelatine with a gel strength between about 10 and about 300 Bloom gel strength units.
For example, gelatine with a gel strength between about 10 and about 100 Bloom gel strength units, such as for providing a gel dosage form (e.g. sachets); or a gelatine with a gel strength above about 100 Bloom gel strength units, such as about 100 to 300 Bloom gel strength units, such as for drops with different solidity/strength.
Said pharmaceutical composition comprising gelatine is preferably in an oral dosage form preferably in the form of a gel, gel caps or jelly beans.
Using gelatine as the pharmaceutical vehicle the drug substance is predispersed in a final application form and released subsequently in the gut and intestinal content. A final drug application form as gel, gel caps or jelly beans may enhance the patient compliance in daily drug intake. Further the gelatine as the drug vehicle increases further the phosphate adsorption, such as shown in example 7d.
The pharmaceutical composition is preferably available in an oral pharmaceutical form.
An (oral) pharmaceutical form according to the invention is preferably selected from granules, tablets, capsules, pills, lozenges, chewable tablets, chewing gum, fruit gum, powder for solution, solutions, dispersions, suspensions, emulsions, and gels. Gels can be gel caps or jelly beans.
In one embodiment the pharmaceutical composition is available in an oral continuous slow-release composition, i.e., an oral composition that ensures continuous slow release or delayed release.
According to the invention, an oral continuous slow-release composition is a composition that continuously releases the active agent into the gastrointestinal tract including the oral environment (oral cavity, saliva).
This also comprises compositions which continuously release the active agent slowly or in a delayed manner, such as chewing gum—provided they are kept in the mouth long enough.
A pharmaceutical form that remains in the mouth long enough allows adsorption of phosphate from the saliva, which can be accomplished for example by chewable tablets with slow release of the active agent. When the pharmaceutical form is administered as a chewing gum, the active agent can remain within the chewing gum and adsorb phosphate from the saliva, thereby eliminating the phosphate when the chewing gum is taken out of the mouth before it reaches the gastrointestinal tract, and/or the active agent is also slowly released from the chewing gum into the saliva, thereby binding the phosphate to prevent enteral absorption.
A drug or a pharmaceutical composition comprises a therapeutically active amount of the active agent (phosphate adsorbent according to the invention). An expert is able to determine the therapeutically active amount required for treatment based on the disease to be treated and the patient's condition. A suitable single dose of a drug or pharmaceutical composition contains approximately between 0.1 and 1000 mg, preferably approximately 10 to 500 mg, of a phosphate adsorbent according to the invention.
The pharmaceutical compositions according to the invention are further characterized in that the active agent (phosphate adsorbent according to the invention) is present in an amount resulting in a concentration range of preferably 0.1 to 100 mM, more preferably 1 to 10 mM in the digestive tract or in biological fluids, when used for in vivo treatment.
In one embodiment, the pharmaceutical composition is available in a pharmaceutical form for parenteral administration, especially intravenous administration.
As described hereinabove, mixtures of aliphatic or cyclic mono- or disaccharides with mannitol are especially preferred for coating (ii) when a pharmaceutical composition for parenteral (especially intravenous) administration is prepared.
Drops in serum phosphate levels are known adverse effects of iron preparations used for intravenous treatment of anemia.
The phosphate adsorbent according to the invention, when provided in a pharmaceutical form for parenteral, especially intravenous administration, is suitable for short-term reduction of the serum phosphate level in severe imbalance after IV treatment with said iron preparations.
See example 7. Example 7 shows phosphate adsorption in serum comparing the phosphate adsorbent according to the invention (from example 1) with a commercially available drug on the basis of inverse spinel iron oxide (with larger particles compared with particle size according to the invention) with a (strongly) stabilizing coating of carboxymethyl dextran (Feraheme®). Feraheme® shows very much lower phosphate adsorption in serum than the phosphate adsorbent according to the invention (from example 1). Here, the phosphate adsorbent according to the invention (from example 1) is a stable aqueous dispersion allowing parenteral, particularly intravenous administration.
Medical Uses
The object is solved according to the invention by providing the phosphate adsorbent according to the invention or the pharmaceutical composition according to the invention for use as a pharmaceutical.
The object is solved according to the invention by providing the phosphate adsorbent according to the invention or the pharmaceutical composition according to the invention for use in the prevention and/or treatment of hyperphosphatemia.
A “phosphate adsorbent according to the invention” refers to a phosphate adsorbent as described herein and to a phosphate adsorbent obtained by a method according to the invention as described herein.
The phosphate adsorbent according to the invention or the pharmaceutical composition according to the invention is preferable available in a dosage form/formulation (suitable) for oral and/or intravenous administration.
In one embodiment, the phosphate adsorbent according to the invention or the pharmaceutical composition according to the invention is provided for                selective removal or elimination of inorganic phosphate from fluids such as hemodialysis fluids, whole blood, or plasma, or from foods,        lowering of serum phosphate levels,        removal of phosphate from saliva,        maintaining a physiological (serum) phosphate level        
in a subject in need of such treatment. These are patients with impaired renal function/chronic renal disease without or with need for hemodialysis.
The use of phosphate binders on the basis of iron oxide crystals has several advantages for patients with impaired renal function. Medications on the basis of iron for treating hyperphospatemia can be manufactured at low cost, and adverse events are not likely to occur. Patients on hemodialysis generally require iron replacement therapy since considerable amounts of iron are eliminated by hemodialysis treatment. Hence, potential gastrointestinal absorption of small amounts of iron is not an undesired adverse effect. On the contrary, it even has a therapeutic benefit in this patient population compared with the undesired risks associated with aluminium, calcium, or lanthanide from other phosphate binders.
In one embodiment, the phosphate adsorbent according to the invention or the pharmaceutical composition according to the invention is provided for                short-term lowering of the phosphate serum level,        
in particular via parenteral administration, more particularly intravenous administration.
In one embodiment, the phosphate adsorbent according to the invention or the pharmaceutical composition according to the invention is provided for the treatment of humans and/or animals.
Formulations with Fructans as Pharmaceutical Excipient (iii)
The present invention further provides pharmaceutical compositions comprising an active agent and a pharmaceutical excipient selected from fructans, such as inulin, and gum arabic or mixtures thereof, and optionally one or several further pharmaceutical excipients.
The pharmaceutical compositions preferably comprise a mixture of fructan (especially inulin) and gum arabic.
Preferred are galenic formulations.